The brain, more than any other organ in the body, depends, for its survival and proper functioning, on a relatively constant supply of oxygenated blood. While comprising only 2% of the body's weight, the brain receives 15% of the heart's output of blood and consumes 20% of the oxygen used by the body. In addition, a constant supply of blood is required to provide the brain with glucose, the major energy substrate used by the brain to produce high energy phosphates such as ATP.
Ischemia may be defined as the loss of blood flow to a tissue. Cerebral ischemia is the interruption or reduction of blood flow in the arteries feeding the brain, usually as a result of a blood clot (thrombus) or other matter (embolus) occluding the artery. Loss of blood flow to a particular vascular region is known as focal ischemia; loss of blood flow to the entire brain, global ischemia.
Once deprived of blood--and, hence, oxygen and glucose--brain tissue may undergo ischemic necrosis or infarction. The metabolic events thought to underlie such cell degeneration and death include: energy failure through ATP depletion; cellular acidosis; glutamate release; calcium ion influx; stimulation of membrane phospholipid degradation and subsequent free-fatty-acid accumulation; and free radical generation.
Knowledge of these underlying events has led investigators studying certain types of ischemic injury to utilize agents such as calcium channel blockers, glutamate and glycine antagonists, CDP-amines, free radical scavengers/antioxidants, perfluorocarbons and thrombolytic agents to improve cerebral blood flow and/or neurological outcome, all with mixed results. Indeed, some vasodilators may improve blood flow and, thus, may find use as anti-ischemic agents. None, however, has been shown to reduce infract volume, particularly in patients that have suffered an ischemic stroke. Conversely, although certain calcium-channel blockers have been reported to decrease infarct size, these drugs also have been reported to produce inconsistent results and undesirable side effects, such as reduction in pulse or perfusion pressure. See, e.g., Kaste, M. et al. Stroke (1994) 25:1348-1353.
More particularly, glutamate antagonists have been observed to reduce infarct size under certain experimental conditions. See, e.g., Olney, J. W. et al. Science (1991) 254:1515-1518. However, most, if not all, of these compounds cause brain vacuolization and most produce phencyclidine-like subjective effects in animals and humans. Ingestion of phencyclidine has been associated with euphoria, anxiety, mood lability and prolonged psychosis.
Free radical scavengers/antioxidants are a heterogenous group of compounds. In general, the effects of these compounds on infarct volume have been inconsistent. For example, superoxide dismutase inhibitors have been found to reduce infarct volume only when injected intracerebroventricularly. See, Kinouchi, H. et al. Proc. Natl. Acad. Sci. USA (1991) 88:11158-11162. Other compounds, such as lubeluzole, have been shown to have clinical benefit but with a very narrow margin of safety. See, Diener, H. C. et al. Stroke (1995) 26:30.
Although perfluorocarbons have shown some benefit in the outcome from ischemic stroke, these compounds have an extremely long half-life and must be infused into the brain and spinal fluid. In addition, these compounds have been observed to cause gonadal hypertrophy. See, Bell, R. D. et al. Stroke (1991) 22:80-83!.
Thrombolytic agents, such as t-PA (tissue plasminogen activator), streptokinase, and urokinase, have shown some promise in the treatment of ischemia. However, these agents have the propensity to increase intracranial bleeding, which, ultimately, can lead to increased mortality. See, e.g., del Zoppo, G. J. et al. Seminars in Neurology (1991) 11(4):368-384; The Ancrod Stroke Study Investigators, Stroke (1994) 25:1755-1759; Hacke, W. et al. Stroke (1995) 26:167. Moreover, the efficacy of these agents may be limited to treatment within the first three hours of stroke.
Citicoline monosodium is an exogenous form of cytidine-5'-diphosphocholine (CDP-choline). Endogenous CDP-Choline is a key intermediate in the biosynthesis of membrane phosphatidyl choline, which is of primary importance for the dynamic regulation of cellular integrity. The role of phospholipids in the maintenance of neuronal function is critically important in conditions where ischemia can induce the breakdown of these membranes.
Citicoline has been extensively studied in clinical trials. Results of these trials indicated an improvement in a variety of clinical symptoms, including headache, vertigo, motor coordination and insomnia. These trials also showed improvements in motor function and reduction in stroke sequelae. However, such trials were limited to the use of citicoline during the rehabilitation stage of patients who may have suffered a stroke, and, thus, such treatments occurred well after the putative ischemic event. Nevertheless, such trials showed that stroke and head trauma patients tolerated citicoline well at dose ranges of 250 mg/day to 1000 mg/day for several weeks.
The inventors believe that the full potential therapeutic effects of citicoline, which may be related to membrane stabilization through enhanced phospholipid synthesis in ischemic brain, have not been realized in prior studies because such studies involved the administration of citicoline well after the onset of ischemia, typically only during the treatment efforts to foster recovery of the patient. Furthermore, such prior treatments may not have proceeded for sufficiently long enough periods.
Stroke is a severe, potentially catastrophic disease affecting approximately 500,000 people per year in the U.S. Clinicians have had to rely on supportive measures and non-specific agents, such as steroids and mannitol, to reduce brain swelling. As 25 to 50% of stroke victims become disabled, there exists a need for improved methods of treating these patients.
Although intravenous thrombolytic therapy has shown some promise if administered within three hours of a stroke, it is believed that an oral drug treatment that would be initiated within a 24-hour post-stroke window and which would positively affect neurological outcome three months after a stroke could become an important new weapon in the fight against this disease.